eLife (Aug 2015)
A molecular tweezer antagonizes seminal amyloids and HIV infection
- Edina Lump,
- Laura M Castellano,
- Christoph Meier,
- Janine Seeliger,
- Nelli Erwin,
- Benjamin Sperlich,
- Christina M Stürzel,
- Shariq Usmani,
- Rebecca M Hammond,
- Jens von Einem,
- Gisa Gerold,
- Florian Kreppel,
- Kenny Bravo-Rodriguez,
- Thomas Pietschmann,
- Veronica M Holmes,
- David Palesch,
- Onofrio Zirafi,
- Drew Weissman,
- Andrea Sowislok,
- Burkhard Wettig,
- Christian Heid,
- Frank Kirchhoff,
- Tanja Weil,
- Frank-Gerrit Klärner,
- Thomas Schrader,
- Gal Bitan,
- Elsa Sanchez-Garcia,
- Roland Winter,
- James Shorter,
- Jan Münch
Affiliations
- Edina Lump
- Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany
- Laura M Castellano
- Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States; Pharmacology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States
- Christoph Meier
- Institute of Organic Chemistry III/Macromolecular Chemistry, Ulm University, Ulm, Germany
- Janine Seeliger
- Physical Chemistry I—Biophysical Chemistry, Department of Chemistry and Chemical Biology, Technical University of Dortmund, Dortmund, Germany
- Nelli Erwin
- Physical Chemistry I—Biophysical Chemistry, Department of Chemistry and Chemical Biology, Technical University of Dortmund, Dortmund, Germany
- Benjamin Sperlich
- Physical Chemistry I—Biophysical Chemistry, Department of Chemistry and Chemical Biology, Technical University of Dortmund, Dortmund, Germany
- Christina M Stürzel
- Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany
- Shariq Usmani
- Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany
- Rebecca M Hammond
- Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States; Biology Department, Swarthmore College, Swarthmore, United States
- Jens von Einem
- Institute of Virology, Ulm University Medical Center, Ulm, Germany
- Gisa Gerold
- Institute of Experimental Virology, Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany
- Florian Kreppel
- Institute of Gene Therapy, Ulm University Medical Center, Ulm, Germany
- Kenny Bravo-Rodriguez
- Max-Planck-Institut für Kohlenforschung, Mülheim an der Ruhr, Germany
- Thomas Pietschmann
- Institute of Experimental Virology, Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany
- Veronica M Holmes
- Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States
- David Palesch
- Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany
- Onofrio Zirafi
- Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany
- Drew Weissman
- Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States
- Andrea Sowislok
- Department of Chemistry, University of Duisburg-Essen, Essen, Germany
- Burkhard Wettig
- Department of Chemistry, University of Duisburg-Essen, Essen, Germany
- Christian Heid
- Department of Chemistry, University of Duisburg-Essen, Essen, Germany
- Frank Kirchhoff
- Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany; Ulm-Peptide Pharmaceuticals, Ulm University, Ulm, Germany
- Tanja Weil
- Institute of Organic Chemistry III/Macromolecular Chemistry, Ulm University, Ulm, Germany; Ulm-Peptide Pharmaceuticals, Ulm University, Ulm, Germany
- Frank-Gerrit Klärner
- Institute of Organic Chemistry, University of Duisburg-Essen, Essen, Germany
- Thomas Schrader
- Department of Chemistry, University of Duisburg-Essen, Essen, Germany
- Gal Bitan
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States; Brain Research Institute, University of California at Los Angeles, Los Angeles, Los Angeles, United States; Molecular Biology Institute, University of California, Los Angeles, United States
- Elsa Sanchez-Garcia
- Max-Planck-Institut für Kohlenforschung, Mülheim an der Ruhr, Germany
- Roland Winter
- Physical Chemistry I—Biophysical Chemistry, Department of Chemistry and Chemical Biology, Technical University of Dortmund, Dortmund, Germany
- James Shorter
- Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States; Pharmacology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States
- Jan Münch
- Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany; Ulm-Peptide Pharmaceuticals, Ulm University, Ulm, Germany
- DOI
- https://doi.org/10.7554/eLife.05397
- Journal volume & issue
-
Vol. 4
Abstract
Semen is the main vector for HIV transmission and contains amyloid fibrils that enhance viral infection. Available microbicides that target viral components have proven largely ineffective in preventing sexual virus transmission. In this study, we establish that CLR01, a ‘molecular tweezer’ specific for lysine and arginine residues, inhibits the formation of infectivity-enhancing seminal amyloids and remodels preformed fibrils. Moreover, CLR01 abrogates semen-mediated enhancement of viral infection by preventing the formation of virion–amyloid complexes and by directly disrupting the membrane integrity of HIV and other enveloped viruses. We establish that CLR01 acts by binding to the target lysine and arginine residues rather than by a non-specific, colloidal mechanism. CLR01 counteracts both host factors that may be important for HIV transmission and the pathogen itself. These combined anti-amyloid and antiviral activities make CLR01 a promising topical microbicide for blocking infection by HIV and other sexually transmitted viruses.
Keywords
